Celiac Disease 2017:

Just the Tip of the Iceberg

Amar R. Deshpande MD

Associate Professor of Medicine

Asst Dean for Medical Education

Vice Chief for Education, Division of Gastroenterology

University of Miami Miller School of Medicine

What celiac disease is NOT

IBS (or FGID Rome IV)

Non-immunologic food response

◦ GI disorders (disaccharidase deficiency)

◦ Intolerances (EtOH)

◦ Poisoning (Ciguatera)

Wheat allergy

An “allergy” at all

◦ IgE, rapid onset, systemic

Non-celiac gluten sensitivity

Why me?

Great question

Much more an “inflammatory bowel

disease” than an “allergy”

◦ autoimmune

◦ mucosal immunology

◦ microbiome, hygiene

Objectives

Appreciate the history and epidemiology

of celiac disease

Understand the pathophysiology and

diagnosis of celiac disease

Be aware of the potential complications

of the disease and the reasons for failing

conventional treatment

Know the current treatment paradigm

and future therapeutic options

Celiac Disease

condition of the small bowel in which

genetically susceptible individuals develop

an immune-mediated enteropathy due to

a sensitivity to gluten

this leads to mal-assimilation of both

micro- and macro-nutrients

with continued exposure to gluten, celiac

disease becomes self-perpetuating and

becomes harder to treat over time

History

koiliakos suffering in the bowels

◦ first described by Aretaeus of Cappadocia

~200 CE

◦ Francis Adams’ translation to English in 1856

at the Syndenham Society described a series

of patients with chronic relapsing steatorrhea,

weight loss, and pallor

Adams F. On The Cœliac Affection: The extant works of Aretaeus the Cappadocian. 1856. London: Sydenham Society.

History

In 1888, pediatrician Samuel Gee noted a

likely dietary component in children in his

translation of Aretaeus’ work

In 1908, American Christian Herter

noted better tolerance of fats than

carbohydrates in children with this

syndrome Gee-Herter disease

Gee SJ. St Bartholomew's Hospital Report 1888;24:17-20.

Herter CA. On infantilism. 1908. New York: Macmillan & Co.

History

Following the Dutch famine of 1944,

during which flour was sparse, Dr. Willem

Dicke noted improvement in children’s

symptoms

In 1952, English researchers linked celiac

disease to gluten insensitivity

Later work showed the role of small

bowel biopsy in making a diagnosis

Dicke WK. Celiac: an investigation into the injurious influence of different kinds of grain to the sufferer of celiac

(translated). 1950. Utrecht, the Netherlands.

van Berge-Henegouwen G. Gut 1993;34(11):1473–5.

Anderson C. Lancet 1952;1(17):836-42.

Epidemiology

Incidence has dramatically risen with the

advent of endoscopic biopsies and

effective serologic markers

◦ 1:130 – 1:300 in European studies (higher in

Northern Europe and Scandanavia)

◦ series from Africa, South America, and Asia are

now showing similar incidences in parts of the

world previously thought less affected

Catassi C. Lancet 1994;343(8891):200-3. Catassi C. Lancet 1999;354(9179):647-8.

Gandolfi L. Am J Gastroenterol 2000;95(3):689-92. Sood A. Am J Gastroenterol 2001;96(9):2804-5.

The Iceberg

Maki M. Lancet 1997;349(9067):1755-9.

abnormal

serologies

So there were >2 million Americans projected with celiac disease, of

which ~40K had been diagnosed for every 1 patient with celiac

disease, there were 53 undiagnosed patients*

Total Screened

13145

Not At Risk 4126

CD+

31

CD-

4095

At Risk

9019

Symptoms+ 3236

CD+

81

CD-

3155

1° relatives 4508

CD+

205

CD-

4303

2° relatives 1275

CD+

33

CD-

1242

Prevalence 1:133

Prevalence 1:40

Prevalence 1:22

Prevalence 1:39

Fasano A. Arch Intern Med 2003;163(3):286-92. * Hamilton FA, NIH/NIDDK

Prevalence ~31K people <50 years old living near Mayo (MN)

had blood test for celiac disease (TTG IgA) with

confirmatory test (AEM IgA); none had known

celiac

Compared comorbidities between undiagnosed

celiac and age/sex-matched controls (nested case-

control)

Prevalence of undiagnosed celiac 1.1%

◦ not associated with diarrhea, anemia, fracture, mortality

◦ increased hypothyroidism, lower cholesterol and ferritin

5 year cumulative incidence of celiac disease

thereafter 11% compared to 0.1% in seronegative

people RS Choung. Gastroenterology 2017;152:830-9.

Pathophysiology

In the appropriate genetic host, proteins to which those with celiac disease are intolerant induce T-cell activation and T-cell mediated inflammation of the small bowel

HLA MHC Class II molecules DQ2 or DQ8 are necessary for phenotypic expression

◦ HLA DQ2 is found in 90-95% of patients

◦ HLA DQ8 is found in the other 5-10% of patients

◦ new GWAS have found several other non-HLA variants in regions of immune function

Sollid LM. J Exp Med 1989;169(3):345-50. Dubois PC. Nat Genet 2010;42(4):295-302.

Pathophysiology

Intolerance to gluten – the protein mass left after starch is washed from dough

Actually, it is an intolerance to the “prolamins;” proteins with high concentrations of proline and glutamine

◦ gluten (of which gliadin is the alcohol-soluble portion) is the wheat protein

◦ hordein is the protein of barley, and secalin is the rye protein

Therefore, those with celiac disease are intolerant of wheat, barley, and rye

What about oats?

Studies have looked at oat protein (avenin):

◦ most show NO immune-mediated

inflammatory response to avenin alone

◦ much of the prior concern with oats was likely

due to cross-contamination in mills harvesting

wheat, barley, and/or rye

Corn (zein), rice, potato, and soy proteins

similarly do NOT induce an autoimmune

response less prolamin effect?

Garsed K. Scand J Gastroenterol 2007;42(2): 171–8. Högberg L. Gut 2004;53(5):649-54.

Kilmartin C. Gut 2003;52(1): 47–52. Janatuinen EK. N Engl J Med 1995;333(16): 1033–7.

Srinivasan U. BMJ 1996;313(7068): 1300–1. Hoffenberg EJ. J Pediatr 2000;137(3): 361–6.

Pinto-Sanchez MI. Gastroenterology 2017;153(2):395-409.

Pathophysiology

Lack of prolyl endopeptidases in human small bowel prevents digestion of proline-rich proteins (prolamins)

In the presence of tissue transglutaminase (TTG), the glutamines are deamidated to negatively charged glutamic acid

In these long polypeptides, correct spacing of prolines and glutamates can bind to HLA DQ2 and DQ8 on APCs in the lamina propria

Pathophysiology

This complex activates CD4+ T-cells and IFN-γ

in the intestinal mucosa, initiating the

inflammatory response

The negatively charged prolamins have also

been shown to induce IL-15 in enteric epithelial

cells, stimulating proliferation of NK cells

There are also large amounts of CD8+ T-cells in

the intestinal epithelium

Villous atrophy and crypt hyperplasia then lead

to B cell activation and antibody production

◦ including antibodies against TTG, endomysium

Farrell RJ. New Engl J Med 2002;346(3):180-8. Green PH. New Engl J Med 2007;357(17):1731-43.

Sollid LM. Nat Rev Immunol

2013;13(4):294-302.

Pathophysiology

In controls, competent intercellular tight junctions in the small bowel limit prolamin passage across the intestinal epithelial barrier

In celiac patients, however, gliadin co-localizes with CXCR3 on the apical side, recruiting receptor MyD88

This induces release of zonulin, which increases permeability and allows further passage of prolamins

Lammers KM. Gastroenterology 2008;135(1):194-204.

Pathophysiology

The resultant inflammatory cascade leads

to enteritis

◦ the villi atrophy, eventually manifested as

scalloping of the folds

◦ this leads to inadequate nutrient assimilation

and resultant nutritional deficiencies

iron, folate, calcium, Vitamin D, magnesium, zinc

B12 and Vitamin K less common (ileum

uncommonly involved in celiac sprue)

continued mucosal damage leads to mal-assimilation

of fats, proteins, and carbohydrates

Pathophysiology >35% of white Northern Europeans are DQ2+,

as opposed to 15% of black South Africans

So what makes only certain DQ2/DQ8 people susceptible? ◦ how and when prolamin sensitivity occurs is unknown

◦ this seems to trigger an autoimmune response to TTG, making the intestinal barrier more susceptible to prolamins and causing a vicious cycle

◦ role of early exposure to wheat?

◦ ? initial enteric infection triggering differing immune response to gluten

◦ ? differing ability to co-localize with CXCR3

◦ different microbiota differences in prolamin permeability of intestinal barrier and immunogenicity

Paul T. UCLA Tissue Typing Laboratory, LA:1997;427–60. Caminero A. Gastroenterology 2016;151:60-83.

Bouziat R. Science 2017;356:44-50. Kemppainen KM. Clin Gastroenterol Hepatol 2017;15(5):694-702.

Microbiome and Hygiene

http://www.intratext.com/ixt/_EXT-REP/_P2R.HTM

Pathophysiology

Trigger: is it timing of initial gluten

exposure or duration of breastfeeding?

Data conflicting:

◦ higher incidences of CD in those exposed to

cereals at <3 months compared to those

exposed to cereals at 3-6 months

◦ higher incidences of CD in those NOT exposed

to cereals until >7 months

◦ higher incidences of CD in those NOT exposed

to cereals until >6 months AND in those

breastfed >12 months

Norris JM. JAMA 2005;293(19):2343-51. Auricchio S. J Pediatr Gastroenterol Nutr 1983;2:428-33.

Ivarsson A. Am J Clin Nutr 2002;75:914-21. Stordal K. Pediatrics. 2013;132(5):e1202-9.

Timing of gluten exposure –

more questions than answers

475 kids randomized: gluten at weeks 16-24 vs placebo

◦ All DQ2 or DQ8 + with one 1st degree relative with CD

◦ No difference in TTG in 2 groups, and at 3 years no

reduction of risk in biopsy-proven CD

800 newborns with 1st degree relative with CD got gluten

at 6 months (A) vs 12 months (B); those with HLA risk

alleles stayed in the trial

◦ At 2 years more +Abs and CD in A but that went away

at 5 and 10 years

◦ Risk mostly driven by HLA risk rather than time of

gluten exposure

So no clear idea of when to start gluten

Lionetti E. N Engl J Med 2014:371(14):1295-303.

Vriezinga SL. N Engl J Med 2014;371(14):1304-15.

TEDDY Study

Pediatrics, January 2015

◦ Multiple countries

◦ Gluten introduction <17 weeks or >26

weeks not an independent risk factor

for developing celiac disease

adjusted for country, HLA, gender, and FH of celiac,

neither in overall nor country-level comparison

Aronsson CA. Pedatrics 2015;135(2):239-45.

From TEDDY, maybe it’s not when but how much: increased intake

in first 2 years of life increased risk 2 fold (mostly intake after

age 1 and CD occurred later in life)

March 2016

The risk of inducing CD through a gluten-containing diet exclusively applies to persons carrying at

least one of the CD risk alleles. Because genetic risk alleles are generally not known in an infant at

the time of solid food introduction, the following recommendations apply to all infants,

although they are derived from studying families with first-degree relatives with CD. Although

breast-feeding should be promoted for its other well-established health benefits, neither any

breast-feeding nor breast-feeding during gluten introduction has been shown to reduce

the risk of CD. Gluten may be introduced into the infant's diet anytime between 4 and 12

completed months of age. In children at high risk for CD, earlier introduction of gluten (4 vs 6

months or 6 vs 12 months) is associated with earlier development of CD autoimmunity (defined as

positive serology) and CD, but the cumulative incidence of each in later childhood is similar. Based

on observational data pointing to the association between the amount of gluten intake and risk of

CD, consumption of large quantities of gluten should be avoided during the first weeks

after gluten introduction and during infancy. The optimal amounts of gluten to be introduced

at weaning, however, have not been established.

Presentation

Presentation

Typical symptoms

◦ in children: diarrhea, stunted growth, anemia, failure to

thrive

◦ in adults: diarrhea, flatulence, IDA, weight loss, lactose

intolerance, malaise, abdominal cramping

Celiac disease can present very non-specifically, and it is

critical to consider it prior to a diagnosis of “IBS”

◦ 5-7% of patients with IBS/fibromyalgia actually have celiac disease

compared to <1% in controls

◦ there also exists non-celiac gluten sensitivity

There are myriad extraintestinal manifestations that can

be the initial presentation of celiac disease

◦ many of these are autoimmune in nature

Sanders DS. Lancet 2001;358(9292):1504–8. Rodrigo L. Arthritis Res Ther 2013;15(6):R201.

Diagnosis

In one study, 178/924 patients with CD

developed another autoimmune disease

(~20%)

In another, 23/140 pediatric patients with

autoimmune liver disease had CD

consider CD in cryptogenic liver disease

Cosnes J. Clin Gastroenterol Hepatol 2008;6(7):753-8. Caprai S. Clin Gastroenterol Hepatol 2008;6(7):803-6.

Symptoms and Associated Features

adapted from Farrell RJ. New Engl J Med 2002;346(3):180-8.

Dermatitis herpetiformis

• stains positive for IgA on skin

biopsy

• treated with gluten-free diet (GFD)

and dapsone

adapted from Dermatol Nursing 2004, AAD website

Diagnosis

Duodenal biopsies are the gold standard

Serologies have improved and are now a helpful screening tool

If typical symptoms exist, EGD with biopsy can demonstrate enteritis with villous blunting ◦ serologies can then confirm the diagnosis to rule out

other causes of mal-assimilation

If symptoms are atypical, it is more cost-effective to check serologies ◦ if negative, CD is very unlikely

◦ 10 EGDs are needed to diagnose 1 CD

◦ if serologies are +, then EGD with duodenal biopsy can confirm the diagnosis (if needed)

Rostom A. Gastroenterology 2006;131(6):1981-2002.

Genetics

Most celiac patients are HLA DQ2+ and the rest

are HLA DQ8+

DQ2 and DQ8 genotype testing available

A negative genetic test essentially rules out celiac

disease (NPV ~98-100%)

◦ best used to definitively rule out celiac disease in

those with a low pre-test probability

Lundkin KE. Hum Immunol 1994;41:285-91.

Serologies

• Antireticulin antibodies outdated

• Antigliadin antibodies also too nonspecific. These have been largely

abandoned, though newer antibodies to deamidated gliadin are used

• TTG is the autoantigen for endomysial antibodies

• IgA deficiency is 10x more common in CD (1:40 vs 1:400), so serum IgA

should be checked to prevent false-negative testing (if IgA deficiency

exists, check an IgG anti-TTG)

Farrell RJ. New Engl J Med 2002;346(3):180-8. Rostom A. Gastroenterology 2005;128(S1):S38-S46.

Sugai E. Clin Gastroenterol Hepatol 2006;4(9):1112-7.

Serologies

The TTG antibody is the appropriate first test (or

another marker like AEM or DGP)

◦ only combine tests (panels) if age <2

Antibody-negative CD increases in incidence with age

Increasing antibody titers to TTG are statistically

significantly associated with:

◦ lower BMD

◦ lower hemoglobin

◦ lower BMI

◦ lower total cholesterol

◦ higher random blood glucose

West J. Clin Gastroenterol Hepatol 2007;5(1):59-62.

Rubio-Tapai A. Am J Gastroenterol 2013;108(5):656-76.

Biopsies

Despite improvements in serologic testing, small

bowel biopsies are still the gold standard and

recommended for diagnosis

As celiac disease affects the small bowel in a

proximal distal pattern, EGD is the best

modality to acquire tissue

The nature of mucosal damage is often patchy

◦ sometimes enteroscopy is needed to obtain

diagnostic specimens

Small bowel endoscopy

normal

scalloping of

the small bowel

folds

adapted from www.celiacdiseasecenter.columbia.edu

Microscopy

normal celiac disease

- <30-40 intraepithelial lymphocytes (IELs) per 100 enterocytes versus

increased number

- bland lamina propria (normal) versus dense lymphocytic infiltrate (CD)

- 1:3 crypt to villous ratio versus 1:1

- normal villous height versus blunted

adapted from www.thedaveproject.com

Biopsies – Modified Marsh

(Oberhuber) classification

Marsh MN. Gut 1990;31:111-4

Dickson BC. J Clin Pathol 2006;59:1008-16.

Biopsies

What are the limitations in biopsy?

◦ in a large multicenter study, ~10% of biopsy specimens

were inadequate for diagnosis, mainly due to suboptimal

orientation of the small duodenal specimens

◦ availability of GI pathologists who know the different

criteria and stages of disease

◦ known patchiness of the disease

So how many biopsies are needed?

◦ 4 is best: 2 biopsies confirms diagnosis in 90%, 3 confirms

in 95%, and 4 confirms in 100%

◦ at least 1 in the bulb: sometimes villous atrophy only there

Collin P. Eur J Gastroenterol Hepatol 2005;17(1):85-91. PaisWP. Gastrointest Endosc 2008;67(7):1082-7.

Evans KE. Am J Gastroenterol 2011;106(10):1837-42.

Enteritis

In those with villous blunting, do not forget

other etiologies

◦ Giardia, Whipple disease, tropical sprue,

CVID/HIV enteropathy, IL, eosinophilic

disease, Crohn disease, ZES, SIBO, food

allergies

◦ most of these do NOT have ↑IELs

Wireless capsule endoscopy has an emerging

role in small bowel visualization in

biopsy/serology negative CD no controlled

studies of balloon enteroscopy in this area yet Spada C. World J Gastroenterol 2008;14(26):4146-51.

severe scalloping in mid-small bowel seen on capsule endoscopy

Dickey W. Clin Prac Gastroenterol Hepatol 2006;3(10):546-51.

What about NCGS? Non-celiac gluten sensitivity, ?etiology

◦ better with gluten avoidance but NOT celiac

disease (genetics, serologies, biopsies)

What else does a gluten-free diet change?

◦ fewer FODMAPs? fewer preservatives?

“healthier” diet?

◦ perhaps some immunologic basis

Gluten-free diet may be most popular

diet ever, but not without ?risk

◦ more coronary artery disease?

◦ trace metal imbalance? Lebwohl B.. BMJ 2017;357:j1892.

Whom to screen

concomitant autoimmune disease

1st degree relatives of those with CD

unexplained IDA

unexplained osteoporosis

any of the high-risk groups (one or more

of the associated conditions/features)

NOT in the general population as per

March 2017 USPSTF recommendation USPSTF. JAMA 2017;317(12):1252-7.

Chou R. JAMA 2017;317(12):1258-68.

Treatment

Treatment

Hallmark of treatment is removal of all damage-inducing

prolamins from diet (wheat, barley, rye)

Congress passed the FDA’s Food Allergen Labeling and

Consumer Protection Act (FALCPA) in 2004, requiring

food manufacturers to clearly state if a product contains

any of the eight major food allergens

◦ milk, eggs, peanuts, tree nuts, fish, shellfish, wheat, and soy

◦ it also made more stringent guidelines on what constitutes

“gluten-free”

FINALLY, in August 2013 FDA mandated that “gluten-

free” can only be used if <20 ppm

◦ but some may get symptoms at >1 ppm

www.fda.gov

Forbes GM. Clin Gastroenterol Hepatol 2015;13(3):614-5.

Treatment

Time to symptomatic improvement

◦ days to weeks

Time to serologic conversion

◦ weeks to months

◦ only relevant if pre-GFD serology was +

◦ a non-invasive way of monitoring

improvement/adherence

Time to histologic improvement

◦ months

AGA Patient Info Center, www.gastro.org

Treatment

In those not responding to a gluten-free diet

(GFD), consider:

◦ noncompliance very difficult diet

◦ inadvertent nonadherence

hordein in beer, gliadin in meds and the

sticky part of envelopes/stamps, etc

◦ microscopic colitis (lymphocytic > collagenous)

◦ ulcerative jejunitis multiple SB ulcers

? precursor to EATL

may respond to immunosuppression

Sussman DA. Am J Gastroenterol 2007;102(8):1833-4. Parra J. Dig Dis Sci 2007;52(3):698-701.

MOST

COMMON

ulcerations/erosions in the jejunum seen on capsule endoscopy (ulcerative

jejunitis in a patient with celiac sprue not responding to a GFD)

Dickey W. Nat Clin Prac Gastroenterol Hepatol 2006;3(10):546-51.

Poor response to GFD

concomitant food allergy/IBD

small intestinal bacterial overgrowth

malignancy

◦ enteropathy-associated T-cell lymphoma

(EATL) high mortality

◦ NHL (usually diffuse large B-cell)

◦ small bowel adenocarcinoma

◦ SCC of esophagus and oropharynx are

increased in CD

Refractory sprue

~5% of patients, two types (RCD 1 and 2)

Lose CD8 positivity, clonal expansion of

aberrant IELs ◦ ↑risk of lymphoma

◦ usually responds to steroids

open-capsule budesonide

◦ immunosuppressives and biologics may be needed

long-term

◦ cases of autologous hematopoietic SCT have been

reported

Mauriño E. Am J Gastroenterol 2002;97(10):2595-602. Gillett HR. Gastroenterology 2002;122(3):800-5.

Al-toma A. Blood 2007;109(5):2243-9. Mukewar SS. Am J Gastroenterol epub online 03/21/17

How are we doing?

US diagnosis rates so low in 2004 that NIH convened a

Consensus Development Conference

One CORI database study showed that in patients

undergoing EGD for the following reasons, only:

◦ 10% with anemia

◦ 7% with iron deficiency

◦ 6% with weight loss

◦ 19% with diarrhea

underwent a duodenal biopsy

We continue to underdiagnose this common disease!!

James SP. Gastroenterology 2005;128(4):S1-9. Harewood GC. Am J Gastroenterol 2004;99(9):1790-4.

Future Therapies

Zonulin inhibition

◦ Multicenter, randomized, double-blind, placebo-

controlled study

◦ Larazotide acetate 0.5, 1, or 2 mg 3 times daily

342 adults with celiac disease on a GFD for ≥12 months

4-week placebo run-in, 12 weeks treatment, 4-week placebo

run-out

Primary endpoint: difference in symptoms (Celiac Disease

Gastrointestinal Symptom Rating Scale score)

met with the 0.5-mg dose by mITT with decrease in non-GI symptoms too

1- and 2-mg doses no different than placebo, safety comparable to placebo

Leffler DA. Gastroenterology 2015;148:1311-9.

Future Therapies

Chemokine trafficking antagonism

◦ CCR9 oral inhibitor CCX282-B (Traficet-EN,

ChemoCentryx) originally studied for Crohn disease, now

being evaluated for celiac disease

Providing prolyl endopeptidases with food

◦ no difference in symptoms, ↓fecal fat

◦ perhaps as on-demand therapy for inadvertent consumption

◦ see next slide

Peptide immunotherapy?

◦ there are 3 major peptides in prolamins that elicit the

majority of the immunogenic T-cell response

http://clinicaltrials.gov/ct2/show/NCT00620451 Tye-Din JA. Sci Transl Med 2010;2(41):41ra51.

Salden BN. Aliment Pharmacol Ther 2015;42(3):273-85. Konig J. DDW 2017.

Murray JA. Gastroenterology 2017;152:787-98.

oral combination of two recombinant

gluten-targeting proteases (glutenases)

But symptoms do improve in some

In a post-hoc analysis, patients with celiac

disease who were seropositive despite adhering

to a GFD had significant improvement in

symptoms with latiglutenase

Syage JA. Dig Dis Sci, epub ahead of print 07/28/17.

Vaccine?

Adjuvant-free mix of 3 peptides that

include immunodominant epitopes for

gluten-specific CD4-positive T cells

Intended to engage and render these T-

cells unresponsive to further antigenic

stimulation

2 Phase 1 studies with apparent safety and

?efficacy, further studies to follow

Goel G. Lancet Gastroenterol Hepatol 2017;2(7):479-93.

Sollid LM. J Intern Med 2011;269(6):604-13.

Besides QoL, do we care?

Rubio-Tapia. Gastroenterology 2009;137(1):88-93.

Sera from >9000 healthy adults at an Air Force base (1948-1954) had

serology testing: 0.2% had celiac disease. 2 recent matched cohorts had 0.8%

and 0.9% prevalence for undiagnosed celiac disease, a >4-fold increase.

HR 3.9,

95% CI 2.0-7.5

Lack of treatment complications

Mortality

◦ large Swedish database (>45,000 cases)

◦ retrospective cohort (~1:5 case:control)

◦ increased all-cause mortality in:

Marsh 3/celiac disease: HR1.39, 95% CI 1.33-1.45

Marsh 1-2/inflammation: HR 1.72, 95% CI 1.64-1.79

Marsh 0/latent celiac disease: HR 1.35, 95% CI 1.14-1.58

◦ caveat: absolute mortality risk small

If persistent villous atrophy increased

lymphoma

Ludvigsson JF. JAMA 2009;302(11):1171-8. Lebwohl B. Ann Intern Med 2013;159:169-75.

Recent Review

Leonard MM. Celiac Disease and Nonceliac

Gluten Sensitivity: A Review. JAMA

2017;318(7):647-56.

Some patient resources:

celiac.org

beyondceliac.org

csaceliacs.org

americanceliacsociety.org

THANK YOU!